Brain Transcriptomic and Metabolic Alternation Following a Mediterranean-Ketogenic Diet via Gut-Biome-Brain Mechanisms in a Preclinical Alzheimer’s Model

Objectives: To examine the effect of a Mediterranean-ketogenic diet (MkD) versus a Western-style diet (WD) on the brain metabolome and transcriptomic profiles in a transgenic murine model of Alzheimer's disease. Methods: Wild-type (WT) and double-transgenic (APP/PS1) mice (AD) (n=8-9/group) were fed either a WD or MKD diet for 8-weeks. Brains were harvested at the end of the dietary intervention to measure metabolite receptors, Alzheimer's pathologic markers (Amyloid-β and tau proteins), and inflammatory markers using Western blotting. Brain metabolomes were quantified by NMR spectroscopy. Hippocampal RNA transcriptomics analysis was performed using the NanoString nCounter system to assess neuroinflammation pathways genes. Results: In preceding study, we observed significant changes in the gut microbiome and gut-plasma metabolite profiles, which were associated with improved neuroinflammation and neurocognitive behavior in AD mice. As lactate levels increased in both the gut and serum, we herein measure its receptor (GPR81) in the brain and find that it tends to increase in MkD-fed mice with nearly significant augmentation in AD mice, indicating that gut-derived metabolites reach the brain and activate receptors closely associated with neurological pathways. Transcriptomics analyses reveal that mice within the same genotype-diet group share similar pathway profiles. Notably, MkD tends to upregulate functional pathways such as astrocyte function, matrix remodeling, autophagy, and angiogenesis in AD mice. Additionally, metabolite profiling shows increased neurotransmitter-related metabolites such as aspartate, glutamate, and glutamine in MkD-fed AD mice. Conversely, metabolic by-products like N-butyrylglycine and 3-Hydroxyisovalerate, as well as energy metabolism-associated metabolites such as creatine and hypoxanthine, are increased in WD-fed AD mice. While no significant differences are seen in AD pathologies among the groups, phosphorylated-tau is marginally decreased in MkD-fed AD group. Conclusions: Specific microbiome-derived metabolites following MkD may be transported to the brain via the gut-blood-brain channel and enhance brain function by improving functional pathways via regulating specific transporters and receptors, including GPR81. Funding Sources: Florida State University Council on Research & Creativity.